Sepsis is characterized by the release of bacterial structural components and toxins that activate inflammatory cascades in target cells. The recruitment of neutrophils and their binding to the vascular endothelium is an important, early response to sepsis. Neutrophils and resident macrophages initiate repair processes via the secretion of cytokines, chemokines and digestive enzymes. Dysregulation of the immune response, however, can lead to widespread and uncontrolled inflammatory injury characterized by leukocytosis (neutrophilia/monocytosis). This dysregulation results in multiple organ dysfunction syndrome (MODS) with the transition to overt septic shock. Respiratory failure progresses rapidly and is associated with approximately 40- 50% mortality. HDL serves as a carrier for diverse proteins, including apolipoprotein (apo) A-I and apoE, that play a role in mediating reverse cholesterol transport. Several studies suggest that apoE exerts anti-inflammatory effects, including the modulation of immune cell function, that are independent of its ability to lower plasma cholesterol levels. In this regard, apoE was recently shown to limit th expansion of hematopoietic stem and multipotential progenitor cells (HSPCs), resulting in a decrease in neutrophil and monocyte proliferation. The inhibitory effect of apoE on leukocyte activation was linked to a reduction in cellular cholesterol content per se. It is proposed that HDL-associated apoE plays a critical role in reducing inflammatory cell injury in the context of sepsis. This protective effect of apoE, however, may be limited by reduced levels of HDL that characterize sepsis. Preliminary data presented in the application show that a synthetic peptide (Ac-hE18A-NH2) that mimics effects of native apoE prevents the activation of leukocytes and improves survival in a rodent model of sepsis. Ac-hE18A-NH2 also induces the release of pre-HDL particles containing the antioxidant paraoxonase and apoE itself. Our data also show that apoE mimetics bind to cell surface proteoglycans and mediate cholesterol efflux from leukocytes, a response that is associated with a reduction in lipopolysaccharide-induced cytokine/chemokine release. In this application, we will test the novel hypothesis that Ac-hE18A-NH2 and related apoE mimetic peptides attenuate sepsis-induced inflammatory injury by inhibiting HSPC expansion and leukocyte proliferation/activation by a mechanism involving a reduction in cellular cholesterol content. Additional studies will test whether in vitro treatment with apoE mimetic peptides alters the phenotype/function of leukocytes isolated from septic patients.